title: Sphingosine-1-Phosphate as a Regulator of Hypoxia-Induced Factor-1α in Thyroid Follicular Carcinoma Cells.
abstract: Sphingosine-1-phosphate (S1P) is a bioactive lipid, which regulates several cancer-related processes including migration and angiogenesis. We have previously shown S1P to induce migration of follicular ML-1 thyroid cancer cells. Hypoxia-induced factor-1 (HIF-1) is an oxygen-sensitive transcription factor, which adapts cells to hypoxic conditions through increased survival, motility and angiogenesis. Due to these properties and its increased expression in response to intratumoral hypoxia, HIF-1 is considered a significant regulator of tumor biology. We found S1P to increase expression of the regulatory HIF-1α subunit in normoxic ML-1 cells. S1P also increased HIF-1 activity and expression of HIF-1 target genes. Importantly, inhibition or knockdown of HIF-1α attenuated the S1P-induced migration of ML-1 cells. S1P-induced HIF-1α expression was mediated by S1P receptor 3 (S1P3), Gi proteins and their downstream effectors MEK, PI3K, mTOR and PKCβI. Half-life measurements with cycloheximide indicated that S1P treatment stabilized the HIF-1α protein. On the other hand, S1P activated translational regulators eIF-4E and p70S6K, which are known to control HIF-1α synthesis. In conclusion, we have identified S1P as a non-hypoxic regulator of HIF-1 activity in thyroid cancer cells, studied the signaling involved in S1P-induced HIF-1α expression and shown S1P-induced migration to be mediated by HIF-1.
authors.affiliation: Department of Biosciences, Åbo Akademi University, Turku, Finland ; Minerva Foundation Institute, Helsinki, Finland.
authors.forename: Veronica
authors.initials: V
authors.lastname: Kalhori
authors.forename: Kati
authors.initials: K
authors.lastname: Kemppainen
authors.forename: Muhammad Yasir
authors.initials: MY
authors.lastname: Asghar
authors.forename: Nina
authors.initials: N
authors.lastname: Bergelin
authors.forename: Panu
authors.initials: P
authors.lastname: Jaakkola
authors.forename: Kid
authors.initials: K
authors.lastname: Törnquist
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D064546:Protein Kinase C beta / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008246:Lysophospholipids; D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D064546:Protein Kinase C beta; D013110:Sphingosine; D058570:TOR Serine-Threonine Kinases; C060506:sphingosine 1-phosphate; C546842:MTOR protein, human